Phase 1 first-in-human clinical study of S-trans, trans-farnesylthiosalicylic acid (salirasib) in patients with solid tumors

• Published in: Cancer chemotherapy and pharmacology 2010, Vol.65 (2), p.235-241
• Main Authors: Tsimberidou, Apostolia Maria, Rudek, Michelle A, Hong, David, Ng, Chaan S, Blair, Jessica, Goldsweig, Howard, Kurzrock, Razelle
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cancer Research; Farnesol - analogs & derivatives; Farnesol - chemistry; Farnesol - pharmacokinetics; Farnesol - therapeutic use; Female; Humans; Lymphoma - drug therapy; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Salicylates - chemistry; Salicylates - pharmacokinetics; Salicylates - therapeutic use; Stereoisomerism; Tumors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-009-1027-4

Purpose This phase I first-in-human trial evaluated salirasib, an S-prenyl derivative of thiosalicylic acid that competitively blocks RAS signaling. Methods Patients with advanced cancers received salirasib twice daily for 21 days every 4 weeks. Doses were escalated from 100 to 200, 400, 600, and 800 mg. Results The most common toxicity was dose-related diarrhea (Grade 1-2, 79% of 24 patients). Other toxicities included abdominal pain, nausea, and vomiting. No Grade 3-4 toxicity was noted. Nineteen (79%) patients had no drug-related toxicity >Grade 1. Dose-limiting toxicity (DLT) was not reached, but all three patients treated with 800 mg experienced Grade 1-2 diarrhea, abrogating dose escalation. Six patients were treated at a dose of 600 mg with no DLTs. Seven (29%) patients had stable disease on salirasib for ≥4 months (range 4-23+). The salirasib pharmacokinetic profile was characterized by slow absorption and a rapid elimination phase following oral administration. Salirasib exposure (C max; day 1 AUCinf vs. day 15 AUC₀₋₁₂ h) was similar between days 1 and 15 (P > 0.05). The T ₁/₂ (mean ± SD) was 3.6 ± 2.2 h on day 1. Conclusions Salirasib therapy was well tolerated. The recommended dose for phase II studies is 600 mg twice daily.